Cohort profile: The Chikwawa lung health cohort; a population-based observational non-communicable respiratory disease study of adults in Malawi.

PURPOSE: The aim of this article is to provide a detailed description of the Chikwawa lung health cohort which was established in rural Malawi to prospectively determine the prevalence and causes of lung disease amongst the general population of adults living in a low-income rural setting in Sub-Saharan Africa. PARTICIPANTS: A total of 1481 participants were randomly identified and recruited in 2014 for the baseline study. We collected data on demographic, socio-economic status, respiratory symptoms and potentially relevant exposures such as smoking, household fuels, environmental exposures, occupational history/exposures, dietary intake, healthcare utilization, cost (medication, outpatient visits and inpatient admissions) and productivity losses. Spirometry was performed to assess lung function. At baseline, 56.9% of the participants were female, mean age was 43.8 (SD:17.8) and mean body mass index (BMI) was 21.6 Kg/m2 (SD: 3.46). FINDINGS TO DATE: The cohort has reported the prevalence of chronic respiratory symptoms (13.6%, 95% confidence interval [CI], 11.9-15.4), spirometric obstruction (8.7%, 95% CI, 7.0-10.7), and spirometric restriction (34.8%, 95% CI, 31.7-38.0). Additionally, an annual decline in forced expiratory volume in one second [FEV1] of 30.9mL/year (95% CI: 21.6 to 40.1) and forced vital capacity [FVC] by 38.3 mL/year (95% CI: 28.5 to 48.1) has been reported. FUTURE PLANS: The ongoing phases of follow-up will determine the annual rate of decline in lung function as measured through spirometry and the development of airflow obstruction and restriction, and relate these to morbidity, mortality and economic cost of airflow obstruction and restriction. Population-based mathematical models will be developed driven by the empirical data from the cohort and national population data for Malawi to assess the effects of interventions and programmes to address the lung burden in Malawi. The present follow-up study started in 2019.

Introduction

Globally, non-communicable respiratory diseases (NCRD) are the third leading cause of non-communicable disease (NCD) mortality, causing an estimated 4 million deaths each year [1]. Amongst the NCRD, asthma and chronic obstructive pulmonary disease (COPD) are the most prevalent, affecting approximately 358 million and 174 million people respectively [2]. Annually, COPD causes 3 million deaths accounting for 6% of all deaths worldwide [2-4]. Furthermore, the deaths from these diseases are rising globally [5] in part due to increased longevity and changes in population structure [6].

The majority of the burden of NCRD mortality and morbidity is in low and middle-income countries (LMIC) [1,7], which now account for 90% of COPD deaths [8]. Several community based studies in LMIC have documented a high prevalence of abnormal lung function, both obstructive and restrictive (low lung volumes) [9-15], whilst several couple have documented low prevalence of COPD [16,17] but high prevalence of respiratory symptoms [17]. In contrast, very few observational cohort studies have reported and described the health and economic burden of NCRD [18,19], especially in LMIC settings. Their prevalence means that there is a pressing need to better document the life course epidemiology and the related health and economic burden of abnormal (obstructive and restrictive) lung function in LMIC [10,11].

Malawi remains one of the poorest countries in the world [20] with 83% of its 18 million inhabitants living in rural areas [21]. With a GDP per capita of $300, over half the households live below the poverty line (using the international poverty line of US$ 1.90 per person per day) [22], and about 50% of the national health expenditure is funded from external donors [23,24]. In common many sub-Saharan African (SSA) countries, Malawi is at the intersection of high rates of communicable respiratory diseases (Tuberculosis (TB), pneumonia), and increasing NCRD [25-27]. Although Malawi has a well-established TB control programme, only 10–20% of patients presenting at primary healthcare facilities with a persistent cough have TB [28]. The prevalence of diagnosed NCRD such as COPD, asthma and pulmonary fibrosis is essentially unknown [29] because lung function testing is not available out with research settings [30]. In Chikwawa where this study is based, lung function testing is not available at primary health facilities or secondary care (Chikwawa District Hospital). There is very limited capacity to perform spirometry in tertiary care, and this is provided by research staff, and for most patients, transport cost would prevent them from travelling to access this.

Recently, however, studies have reported substantial levels of abnormal lung function in Malawi, with spirometric evidence of restrictive and obstructive deficits present in 34.8% (95% CI: 31.7%, 38.0%) and 8.7% (7.0%, 10.7%) of rural adults and 38.6% (34.4%, 42.8%) and 4.2% (2.0%, 6.4%) of urban adults respectively [10,11]. Spirometric deficits were defined according to the NHANES III Caucasian references [31]. What is not known is, whether, and how these spirometric deficits impact on the everyday lives of the country’s people and health system. Potentially, as in other low-income situations, the economic burden of NCRD may have serious adverse outcomes for households including unpredictable household expenditures due to complications and catastrophic health expenditure [32].

To examine the health and economic burden of NCRD, including abnormal lung function in Malawi, our prospective study aims to follow up a population-based cohort of participants in the rural district of Chikwawa, in southern Malawi, who were recruited to a longitudinal follow-up spirometry study conducted between August 2014 and July 2015 (the Chikwawa lung health cohort) [11,15]. The primary objectives of the current study are to; (i) estimate the annualised rate of change in lung function by age and sex as determined by repeating spirometry; (ii) to develop a mathematical population model based on the cohort findings that estimates the life-time health impact of airflow obstruction in Malawian adults in disability-adjusted life years (DALYS); (iii) estimate the health resource use and lifetime costs in the cohort of Malawian adults with airflow obstruction in international dollars (Int$); (iv) produce model estimates of the lifetime cost effectiveness (Int$/DALY) of selected key intervention compared with current practice to define optimum packages of interventions; and (v), recreate these analyses for Malawian adults with low lung volumes. The economic cost will be from a societal perspective and will include health sector costs, patient/family and carer costs and productivity losses [33]. Presently, the Malawian health system recommends the use of salbutamol and beclomethasone inhalers and prednisolone as interventions for chronic asthma management and salbutamol inhalers, prednisolone and hydrocortisone injections as interventions for acute asthma [34] but these interventions are only available in 8% of urban health facilities and 2% of rural health facilities in Malawi [35]. The current study will determine whether the substantial levels of abnormal lung function in Malawian adults are clinically and societally important not only currently, but also in the future by estimating the economic cost of obstructive and restrictive conditions. In addition, the present study will provide a basis for NCRD intervention adoption and implementation within the Malawian health system, society and similar settings.

The aim of this cohort profile paper is to provide a comprehensive description of the Chikwawa lung health cohort as a research resource for potential collaborations, including an overview of the collected data, a description of the baseline characteristics and a summary of the main results published so far.

Cohort description and methods

Setting

The study is currently conducted in Chikwawa district, located in Southern region of Malawi. (see Fig 1).

Fig 1

Districts in Malawi.

Inset map highlights Chikwawa district, the study area. (Created using the open source QGIS ver. 3.8. Zanzibar (QGIS Development Team, 2020, https://qgis.org.

Study population

The Chikwawa lung health cohort was initiated alongside the Cooking and Pneumonia study (CAPS) [11,36] (Trial registered with ISRCTN, number ISRCTN59448623). CAPS was a cluster randomized trial that investigated the health effects of a cleaner-biomass fuel cookstove intervention [36]. The aim of setting up the Chikwawa lung health cohort was to determine the prevalence and determinates of lung disease amongst adults in Chikwawa, rural Malawi [11]. Since inception, two rounds of follow-up studies have been conducted with the Chikwawa lung health cohort aiming to assess the determinants of lung function trajectories as affected by personal air pollutant exposures, including the CAPS cookstove intervention [15]. The current study will provide additional longitudinal data by further following up participants from the Chikwawa lung health cohort who still reside in Chikwawa and who were recruited to the baseline study in 2014–2015 [11] and quantify associated risk factors, health utilisation use and economic burden.

Statistical analyses

The sociodemographic and clinical variables were determined for the sample using frequencies and proportions for categorical variables and means and standard deviation for continuous variables. Chi-square and t test were used to investigate associations between gender and the other variables.

Baseline participant recruitment

The participants were originally recruited in 2014–2015. The participants were selected through random sampling of a list of adults living in each of the 50 villages participating in CAPS [11]. The participants included those who took part in the CAPS intervention and those who did not but resided in villages where the CAPS intervention was being implemented. The list of adults was obtained from local community liaison personnel from each village following a series of community engagement events with the village leaders such as chiefs and other community representatives [11]. The random selection was conducted by an independent statistician at the Burden of Obstructive Lung Disease (BOLD) centre in London in accordance with the BOLD protocol [37]. The identified individuals comprised a population-representative, age and gender stratified, sample of adults who were then invited to participate in the 2014–2015 baseline study. Participants had to provide written informed consent or an independently witnessed thumbprint to be included in the study [11]. Those who were acutely unwell or pregnant women or were non-permanent residents of Chikwawa were excluded from the baseline study [11].

A total of 3000 adults were invited to participate in the baseline study of which 1481 (49.3%) agreed to participate [11]. Participants were stratified into two age groups: 18–39 years and 40 years and above. In order to provide an estimate of chronic airflow limitation prevalence in the stratum with a precision (95% CI) of +3.3% to 5.0% and assuming a prevalence of 10% to 25%, a total sample of 1200 participants was estimated allowing for unequal age and gender distribution, refusals and inability to provide spirometry measurements of acceptable quality [11]. Table 1 below summarises the age and sex characteristics of those who agreed to participate in the study compared to those who did not.

Table 1

Demographic characteristics of cohort participants.

		Consenting participants n = 1481	Selected, did not give consent n = 1519
Age, mean (SD)		43.9 (17.8)	40.3 (16.5)
Age categories years n (%)	<39	685 (46.3%)	765 (50.3%)
	40–49	258 (17.4%)	336 (22.1%)
	50–59	217 (14.7%)	179 (11.8%)
	60–69	161 (10.9%)	150 (9.9%)
	>70	160 (10.8%)	89 (5.9%)
Sex	Female	844 (57.0%)	757 (49.9%)
	Male	637 (43.0%)	762 (50.2%)

Participant tracking and recruitment procedures for the current longitudinal study

In the current study, the adult participants have been tracked from participant logs developed in the original baseline study [11]. The participant log contains the person’s name, study identification number, age, gender and village of residence. Community liaison personnel and chiefs were asked to help identify the household of each study participant to maximise fidelity. Study staff then approached the participant in their households, obtained informed consent, geolocation, and agreed a suitable time to collect the lung function, environmental exposures and socioeconomic data.

How often has the cohort been followed up?

Study participants have been followed up twice prior to the current study. The baseline study was conducted between August 2014 –July 2015 [11] with an aim of determining the prevalence and determinates of lung disease. The first and second follow-up studies were between August 2015 –November 2017 [15] aiming to assess the determinants of lung function trajectories as affected by personal air pollutant exposures, including the CAPS cookstove intervention. The current round of follow-up is taking place between July 2019 –March 2021 (see Fig 2).

Fig 2

Flow chart of participant recruitment and follow-up schedule.

Assessment of exposures

In the baseline study, structured interviews were used to collect data on demographic, socio-economic status, respiratory symptoms, and potentially relevant exposures such as smoking [38,39], household fuels [38,40], environmental exposures [39,41], and occupational history [39,42].

In addition to the data collected for the baseline study in the current 2019–2021 follow up, we are collecting additional data on dietary intakes [39,43], healthcare utilization, cost (medication, outpatient visits and inpatient admissions) and productivity losses.

The following anthropometric measures have been recorded at each phase of follow up: height, weight, hip, waist, and neck circumferences, ulna, and fibula lengths. Lung function (forced expiratory volume in one second [FEV1] and forced vital capacity [FVC]) are measured using the ndd EasyOne Spirometer (ndd Medizintechnik AG, Zurich, Switzerland), before and 15 minutes after administration of inhaled salbutamol (200 μg) administered via spacer device. The contraindications for spirometry include: in the previous three months; thoracic or abdominal surgery, acute coronary syndrome, detached retina or eye surgery; hospitalisation for any other cardiovascular reason in the previous month; final trimester of pregnancy; a resting heart rate > 120 beats per minute and current treatment for tuberculosis [44].

Spirometry has been conducted by trained and certified technicians who received regular feedback on spirogram quality in accordance with the BOLD protocol [37]. The quality of each spirogram has been reviewed and scored based on the American Thoracic Society and European Respiratory Society acceptability and reproducibility criteria [45].

In the current phase of follow-up, verbal autopsies were conducted for the 2014–2015 baseline participants who have died, and a questionnaire was administered to the next of kin for those who were unobtainable due to being no longer resident in Chikwawa. The data and variables collected in the Chikwawa lung health cohort are described in Table 2.

Table 2

Summary of measurements in the Chikwawa lung health cohort.

Phase	Spirometry measured	Anthropometric measured	Questionnaires & tools administered
Baseline 2014–2015 [11]	• Forced vital capacity (FVC)• Forced expiratory volume in 1 second (FEV1)• Forced expiratory volume in 6 seconds (FEV6)	• Weight• Height• Waist & hip circumference	• Socio-economic status• Demographic characteristics• Environmental exposures• Smoking history• History of respiratory disease (Tuberculosis, Asthma and COPD).
First and second follow-up (this follow-up phase was called the CAPS-Adult Lung Health study) 2015–2017 [15]	• FVC• FEV1• FEV6.	• Weight• Height• Waist & hip circumference	• Socio-economic status• Demographic characteristics• Environmental exposures• Smoking history• History of respiratory disease (Tuberculosis, Asthma and COPD).• Personal air pollutant monitoring
Ongoing (this follow-up phase is called Adult Lung Diseases in Malawi study) 2019–2021	• FVC• FEV1• FEV6.	• Weight,• Height;• Ulna & fibula lengths;• Neck, waist & hip circumference.	• Socio-economic status• Demographic characteristics• Environmental exposures• Smoking history• History of respiratory disease (Tuberculosis, Asthma and COPD)• History of health utilization and costs (medication, outpatient & inpatient)• Productivity losses• Household dietary consumption

Ethical approval

The study protocol was approved by the Imperial College Research Ethics Committee (17IC4272) (website: https://www.imperial.ac.uk/research-ethics-committee/committees/icrec/), Liverpool School of Tropical Medicine Research Ethics Committee (19–005) (website: https://www.lstmed.ac.uk/research/research-integrity/research-ethics-committee) and the Malawi College of Medicine Research and Ethics Committee (COMREC, P.03/19/2617) (website: https://www.medcol.mw/college-of-medicine-research-ethics-committee/). Written informed consent was obtained from all the participants in this study for the follow-up and for the second interview and examination.

Participant and public involvement

Participants were not involved in in setting research questions or the outcome measures but have been instrumental in implementation of the study.

Participants and the public were involved in the dissemination of baseline information nationally through the Ministry of Health, and in the Chikwawa community from which the data was collected through the Chikwakwa Health Research Committee and the Chiefs and community leaders from the villages from where we collected our data. These activities have encouraged community buy-in and involvement in the subsequent rounds of follow-up within the cohort.

Findings to date and discussions

The Chikwawa lung health cohort has provided data characterising the burden of chronic respiratory symptoms, abnormal spirometry and air pollution exposures and risk factors from an adult population in Malawi [11,36]. These data have contributed to the understanding of NCRD in LMIC. The baseline characteristics of the Chikwawa lung health cohort when established in 2014–2015 are outlined in Table 3. At baseline, a total of 1481 participants were recruited of which 637 (43.0%) were male and 844 (57.0%) were female [11]. The mean age was 43.9 years (SD: 17.8), mean body mass index (BMI) was 21.6 Kg/m2 (SD: 3.46). Cigarette smoking rates were 22.1% (n = 327) were current or ever smokers of which the majority were men (n = 255, 78.0%). There was no difference in ages between the men and women (see Table 3).

Table 3

Baseline demographic, anthropometric and symptomatic characterises of the Chikwawa lung health cohort collected 2014–2015.

Variable (n)		n (%) (total = 1481)	Male n (%) (total = 637)	Female n (%) (total = 844)	P value (X2)Ψ
Age group (years)	<39	685 (46.3%)	288 (45.2%)	397 (47.0%)	0.150
	40–49	258 (17.4%)	103 (16.2%)	162 (18.4%)
	50–59	217 (14.7%)	110 (17.3%)	110 (12.7%)
	60–69	161 (10.9%)	70 (11.0%)	96 (10.8%)
	>70	160 (10.8%)	66 (10.4%)	99 (11.1%)
BMI ##	Underweight (< 18.5)	182 (13.9%)	84 (13.2%)	98 (11.6%)	<0.001
	Normal weight (≥18.5; <25.0)	950 (72.8%)	465 (73.0%)	485 (57.5%)
	Overweight (≥25.0; <30.0)	133 (10.2%)	36 (5.7%)	97 (11.5%)
	Obese (≥ 30.0)	40 (3.1%)	2 (0.3%)	38 (4.5%)
Smoking	Never	1154 (77.9%)	382 (60.0%)	772 (91.5%)	<0.001
	Current	205 (13.8%)	165 (25.9%)	40 (4.7%)
	Former	122 (8.2%)	90 (14.1%)	32 (3.8%)
Symptoms
Cough on most days of the month for at least three months of the year.		167 (11.3%)	81 (12.7%)	86 (10.2%)	0.148
Usually brings up phlegm from chest		39 (2.6%)	21 (3.3%)	18 (2.1%)	0.221
Wheezing/whistling in chest in the past 12 months in the absence of a cold.		24 (1.6%)	15 (2.4%)	9 (1.1%)	0.082
MRC dyspnoea score II [46,47]: shortness of breath when hurrying on the level or walking up a slight hill.		23 (1.6%)	11 (1.7%)	12 (1.4%)	0.766
Any respiratory symptoms		203 (13.7%)	105 (16.5%)	98 (11.6%)	0.008
Functional limitation: breathing problems interfere with usual daily activities.		44 (3.0%)	21 (3.3%)	23 (2.7%)	0.624
Diagnosed lung disease
Asthma		51 (3.4%)	23(3.6%)	28 (3.3%)	0.868
Asthma, emphysema, chronic bronchitis, or COPD		59 (4.0%)	28 (4.4%)	31 (3.7%)	0.566
Previous TB		47 (3.2%)	16 (2.5%)	31 (3.7%)	0.268

## n = 1341. BMI classification based on WHO guidelines [48].

Comparison of proportions using Pearson’s chi square test.

The frequency of chronic respiratory symptoms and abnormal spirometry

Among the participants at recruitment in 2014–15, with interpretable and reliable spirometry (n = 886) [37], spirometric obstruction (defined as FEV1/FVC < 0.70) and spirometric restriction (defined as FEV1/FVC > 0.70 and post-bronchodilator FVC < 80% predicted) [31] were present in 8.7% (95% CI: 7.0%, 10.7%) and 34.8% (95% CI: 31.7%, 38.0%) of the participants respectively according to the NHANES III Caucasian references [11]. 13.7% reported either having a ‘cough without having a cold’, ‘bringing up phlegm from your chest’, ‘wheezing in your chest’, ‘shortness of breath when hurrying on the level or walking up a slight hill’, or ‘breathing problems interfering with your daily activity’ while 11.3% reported a ‘cough on most days of the month for at least three months per year’. 3.4% were diagnosed with asthma while 4.0% were diagnosed with either asthma, emphysema, chronic bronchitis, or COPD (see Table 3). The 2017 follow-up found that, when compared to the NHANES III African American reference ranges, spirometric obstruction and restriction were present in 11.5% (95% CI: 9.6%, 13.5%) and 7.7% (95% CI: 6.2%, 9.5%) of the participants respectively [15]. For participants who had been followed up in both 2015 to 2017, an overall annual rate of lung function decline in forced expiratory volume in one second [FEV1] of 30.9mL/year (95% CI: 21.6 to 40.1) and forced vital capacity [FVC] by 38.3 mL/year (95% CI: 28.5 to 48.1) has been reported [15].

Presently, we are able to trace over 85% of the participants in the Chikwawa lung health cohort and have invited them to participate in this current phase of follow-up. The ongoing analysis of the data at a later time point for follow up will provide better estimates for annual rate of lung function decline.

Present research plans

The ongoing current phase of follow-up of the Chikwawa lung health cohort will determine the annual rate of decline in lung function as measured through spirometry, morbidity, mortality and economic cost of airflow obstruction and restriction and develop population-based mathematical models driven by the empirical data from the cohort and national population data for Malawi to assess the effects of interventions and programmes to address the lung burden in Malawi. It is expected that this further phase of follow-up will add to the body of knowledge of the life course of NCRD in LMIC and further refine and add to the validity of the health economic models developed.

Strengths and limitations

The Chikwawa lung health cohort appears to be the only one of its kind in a low-income country setting aiming to investigate the economic costs over the life course of non-communicable respiratory disease. This cohort represents an opportunity to develop and model cost-effective interventions and programmes for this setting. The baseline cohort was conducted alongside a rigorously conducted cluster randomised control trial. Despite local complexities, we presently have identified over 85% of the baseline cohort to be included in the current phase of follow-up.

Systematic bias may be introduced through the self-selection of the participants who agreed to take part in the study to date and the migration of individuals from Chikwawa. Although we have been able to track over 85% of the original Chikwawa lung health cohort and have invited them to participate in the current phase of follow-up, the participants who can be traced and from whom data are collected may differ from those who cannot be traced or do not attend follow-up. Similarly, at baseline, the participants who agreed to be consented were slightly older and mainly women. The process of verbal autopsies for those who have died [49], and collection of data from the next of kin of those who have moved away, may shed some light on the status of those who have moved away from Chikwawa and deaths from respiratory causes will be of particular interest in the current follow-up. The other limitation identified in this study is recall bias. This is due to most of the data being collected through administering questionnaires in a structured interview format, one can expect recall bias over the follow-up period. We are using tested and validated tools in addition to well-trained experienced interviewers to minimize this bias.

The main strength of the cohort is the collection of initial objective measures of lung function using spirometry conducted to internationally agreed standards [37,45] and on two further occasions over a 3-year period. This will provide valuable insights into the health relevance and natural history of abnormal lung functions in an LMIC setting. Previous studies in the United States, the United Kingdom and Australia have reported the annual rate of decline of FEV1 in adults to be 18 ml/year standard deviation (SD) = 2.5 [50], 33ml/year (SD = 1.5) [51] and 45ml/year (SD = 83) [52].

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21 Sep 2020

PONE-D-20-12808

Cohort profile: The Chikwawa lung health cohort; a population-based observational non-communicable respiratory disease study of adults in Malawi.

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: 1. An aim of the baseline study was to determining the prevalence and determinates of lung disease. Please clarify the prevalence of major lung diseases in this study, especially those that cause spirometric restriction.

2. For such a cohort study, it might make more sense to add the following: What is the diagnostic rate of COPD and asthma? How aware is the population of these diseases? How popular are lung function tests?

3. Analysis of lung function decline in different diseases and age stratification.

4. Analysis of reasons for reluctance to participate in follow-up.

5. There are obvious errors in the statistics of many demographic data, which need to be further verified in Table 3.

Reviewer #2: Purpose well stated but no justification- include justification (The WHY)

Please include names of Ethical review members

What was the involvement of local researcher

NHANES III – used no mention of limitation/ if appropriate or how it was adjusted for non-Caucasian population.

With over 50% of participants decline to be recruited – there should be information of why? And state if this will bias the study

please include results of lung function test done

Limitation

Recall bias -using tested and validated tools is a strong point.

‘ 13.7% reported either having a ‘cough without having a cold’, ‘bringing up phlegm from your chest’, ‘wheezing in your chest’, ‘shortness of breath when hurrying on the level or walking up a slight hill’, or ‘breathing problems interfering with your daily activity’ ‘- not clear where the figure 13.7% was derived, (was it and or?) please clarify

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Reviewer #1: No

Reviewer #2: No

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12 Oct 2020

12th October 2020.

The Editorial office,

PLOS One.

Dear Editors,

RE: Cohort Profile: The Chikwawa lung health cohort; a population-based observational respiratory disease study in Malawi.

Thank you for your review of the above titled manuscript. This is a response to the queries that were raised through the email received on the 21st September 2020.

The responses are separated by journal and reviewer comments and highlighted in red:

Journal requirements:

1) Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

This has been done; however, we would be more than happy to make further changes if deemed necessary by the editorial team.

2) Please include additional information regarding the interview guide and questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information

The interview questionnaires have been added as supplementary files to the manuscript and labelled accordingly.

3) We note that [Figure(s) 1] in your submission contain [map/satellite] images which may be copyrighted. All PLOS content is published under the Creative Commons Attribution License (CC BY 4.0), which means that the manuscript, images, and Supporting Information files will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution. For these reasons, we cannot publish previously copyrighted maps or satellite images created using proprietary data, such as Google software (Google Maps, Street View, and Earth).

This map was created using the open source QGIS ver. 3.8. Zanzibar (QGIS Development Team, 2020, https://qgis.org). The authors’ own the copyright and PLOS can publish the figure under the Creative Commons Attribution License (CC BY 4.0).

4) We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly.

During the review process at PLOS One, a minimal anonymized dataset for this study was published on Mendeley and is publicly accessible. The DOI has been included in the publication in the supplementary information (S1 File). The data collection tools have been provided in the supplementary information (S2 File).

5) Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript.

This has been done.

Reviewers’ comments

Reviewer #1:

1) An aim of the baseline study was to determining the prevalence and determinates of lung disease. Please clarify the prevalence of major lung diseases in this study, especially those that cause spirometric restriction.

The prevalence of non-communicable respiratory diseases (NCRDs) such as asthma, COPD and pulmonary fibrosis are not documented in Malawi due to limited diagnostic capacity in the country and a lack of studies conducted to determine the prevalence of major NCRDs. A few sentences to this effect have been added to page 5 of the manuscript along with supporting references.

Table 3 reports the proportion of participants at recruitment in 2014 to have respiratory symptoms, and those who had received a diagnosis of asthma or COPD previously.

2) For such a cohort study, it might make more sense to add the following: What is the diagnostic rate of COPD and asthma? How aware is the population of these diseases? How popular are lung function tests?

The proportion of our study participants who had been diagnosed with asthma and COPD at recruitment has been included in the manuscript in Table 3.

The capacity to diagnose COPD and asthma is limited in Malawi because lung function testing in Malawi is not readily available out with research settings. In Chikwawa, lung function testing is not available at primary health facilities or secondary care (Chikwawa District Hospital). There is very limited capacity to perform spirometry in tertiary care (such as Queen Elizabeth Central Hospital), and this is provided by research staff, and for most patients, transport costs would prevent them from travelling to access this. On the other hand, the country has well-established TB control programme thus although the population is aware of respiratory symptoms knowledge and diagnosis of COPD and asthma may be limited. Additional text and citations have been included in the manuscript to explain this state. See page 5.

3) Analysis of lung function decline in different diseases and age stratification.

This paper has presented the overall rate of lung function decline of data collected in 2015 – 2017 (See page 18). In addition, we mention that there were no differences in the rate of decline between age groups or with diagnosed asthma or COPD (numbers were small).

Presently, we are have just finished collecting data for the most recent round of follow-up in August 2020 and are analysing that data. The data from a later time point to the baseline will provide better estimates for the annual rate of lung function decline and will be stratified by diagnosed lung disease and age when presented.

4) Analysis of reasons for reluctance to participate in follow-up.

This will be ascertained, and the results presented in subsequent publications. Analysis of a recent round of follow-up is going on at the moment.

5) There are obvious errors in the statistics of many demographic data, which need to be further verified in Table 3.

All the errors in Table 3 have been corrected. The statistical tests undertaken have also been explained so as to clarify our analysis (see page 8). We apologise if errors remain and would be willing to correct if requested by editorial team.

Reviewer #2:

1) Purpose well stated but no justification- include justification (The WHY)

This has been added. See page 6.

2) Please include names of Ethical review members

The opinions of Ethics Committees are considered to be collective and we consider it unusual to list the names of three Review Committees (Exceeding 80 members in total). Instead we have provided links to the Imperial College Ethics Committee, Malawi College of Medicine ethical bodies and the Liverpool School of Tropical Medicine bodies that approved this study have been included in the manuscript. See page 16.

3) What was the involvement of local researcher?

The study is presently housed within the Malawi-Liverpool Wellcome Trust Clinical Research Programme. MN, SR, RN, SG and JR are affiliated with MLW.

Additional MLW staff involved with the study have been acknowledged in the acknowledgement. See page 26

4) NHANES III – used no mention of limitation/ if appropriate or how it was adjusted for non-Caucasian population.

We have provided the estimates using the NHANES III African American reference ranges for the 2017 follow up. See Page 17. In the limitations we now mention the lack of widely accepted reference equations for sub-Saharan Africa and the noticeable difference in restriction when using the NHANES III equations for African-Americans when compared with American Caucasian equations. We also mention the use of GLI 2012 in the current round of follow-up.

5) With over 50% of participants decline to be recruited – there should be information of why? And state if this will bias the study.

Most of those initially identified to be approached but who did not participate were simply not traceable. We have presented the age and sex characteristics of those who were and were not recruited in 2014. We mention the possible biases associated with this in the limitations. One of the stipulations of the ethical approvals was/is that potential participants are able to refuse to take part without giving reason and therefore we are unable to comment on specific reasons why people declined to take part in the original 2014 study.

In the present round of follow-up, we have been able to follow-up >85% of the participants who participated in the baseline study. See page 18. The analysis of these data is still ongoing since we finished data collection for this round of follow-up in August 2020.

6) Please include results of lung function test done.

We have provided a minimal anonymised dataset containing the results of the lung function tests done. This has been included in the publication in the supplementary files.

Yours Sincerely,

Martin Njoroge (Corresponding Author)

E-mail: martin.njoroge@lstmed.ac.uk

29 Oct 2020

Cohort profile: The Chikwawa lung health cohort; a population-based observational non-communicable respiratory disease study of adults in Malawi.

PONE-D-20-12808R1

Dear Dr. Njoroge,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Alana T Brennan

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

4 Nov 2020

PONE-D-20-12808R1

Cohort profile: The Chikwawa lung health cohort; a population-based observational non-communicable respiratory disease study of adults in Malawi.

Dear Dr. Njoroge:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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Academic Editor

PLOS ONE